Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
The National Cancer Institute has estimated that in the United States alone, 1 in 3 people will be struck with cancer during their lifetime. Moreover, approximately 50% to 60% of people contracting cancer will eventually succumb to the disease. The widespread occurrence of this disease underscores the need for improved anticancer regimens for the treatment of malignancy.
In the past several years, Aurora-A kinase (AurA; official name STK6) has attracted increasing attention because it has been found to be overexpressed in a high percentage of tumors arising in breast, colon, ovary, and other tissues and because it has been shown to function as an oncogene when exogenously expressed in various cell line models. AurA overexpression, whether in naturally occurring tumors or following deliberate overexpression, is associated with increased numbers of centrosomes and multipolar spindles, which arise as a consequence of failed cytokinesis. The temporal and spatial localization of overexpressed AurA is not limited to G2 and M phases at the centrosome, but is also detected throughout the cytoplasm in cells in different phases of the cell cycle. Thus, it is not clear at present whether the transforming activity of AurA arises from hyperactivation of normal AurA substrates, or through anomalous targeting by AurA. Unexpectedly, even over-expression of a kinase-inactive form of AurA can induce supernumerary centrosomes (although it cannot transform cells), supporting the idea that the protein has at least two different functions in regulating centrosome numbers: a kinase function, and a scaffolding function for other proteins. Based on these various properties, AurA is now being actively exploited as a target for development of new anti-cancer agents (reviewed in Andrews, P. D. Aurora kinases: shining lights on the therapeutic horizon? Oncogene 2005; 24:5005-15). The AurA-inhibiting compound developed by Nerviano-MS, currently in clinical trials, has been used in the studies described in Soncini, C. et al. (PHA-680632, a novel Aurora kinase inhibitor with potent anti-tumoral activity. Clin Cancer Res 12: 4080-4089, (2006). Sigma also produces a potent Aur-A inhibitor, Cyclopropanecarboxylic acid {3-[4-(3-trifluoromethyl-phenylamino)-pyrimidin-2-ylamino]-phenyl}-amide (hereafter referred to as C1368.)
Despite millions of dollars being spent each year in efforts to identify effective anti-cancer agents and treatment regimens, cancer has yet to be eradicated and effective treatment regimens that are not overly toxic to the patient are still limited in number. It is clear a need exists for improved anti-neoplastic agents and methods of use thereof for the treatment of malignant disease.